The Budesonide-Hydroxypropyl-β-Cyclodextrin Complex Attenuates ROS Generation, IL-8 Release and Cell Death Induced by Oxidant and Inflammatory Stress. Study on A549 and A-THP-1 Cells

Synthetic glucocorticoids such as budesonide (BUD) are potent anti-inflammatory drugs commonly used to treat patients suffering from chronic inflammatory diseases. A previous animal study reported a higher anti-inflammatory activity with a 2-hydroxypropyl-β-cyclodextrin (HPβCD)-based formulation of BUD (BUD:HPβCD). This study investigated, on cellular models (A549 and A-THP-1), the effect of BUD:HPβD in comparison with BUD and HPβCD on the effects induced by oxidative and inflammatory stress as well as the role of cholesterol. We demonstrated the protective effect afforded by BUD:HPβCD against cytotoxicity and ROS generation induced by oxidative and inflammatory stress. The effect observed for BUD:HPβCD was comparable to that observed with HPβCD with no major effect of cholesterol content. We also demonstrated (i) the involvement of the canonical molecular pathway including ROS generation, a decrease in PI3K/Akt activation, and decrease in phosphorylated/unphosphorylated HDAC2 in the effect induced by BUD:HPβCD, (ii) the maintenance of IL-8 decrease with BUD:HPβCD, and (iii) the absence of improvement in glucocorticoid insensitivity with BUD:HPβCD in comparison with BUD, in conditions where HDAC2 was inhibited. Resulting from HPβCD antioxidant and anticytotoxic potential and protective capacity against ROS-induced PI3K/Akt signaling and HDAC2 inhibition, BUD:HPβCD might be more beneficial than BUD alone in a context of concomitant oxidative and inflammatory stress.

Investigating the Phospholipid Effect on the Bioaccessibility of Rosmarinic Acid-Phospholipid Complex through a Dynamic Gastrointestinal in Vitro Model

Phyto-phospholipid complexes have been developed as a common way of improving the oral bioavailability of poorly absorbable phyto-pharmaceuticals; however, the complexation with phospholipids can induce positive or negative effects on the bioaccessibility of such plant-derived active ingredients in different parts of the gastrointestinal tract (GIT). The purpose of this study was to investigate the effects of phospholipid complexation on the bioaccessibility of a rosmarinic acid-phospholipid complex (RA-PLC) using the TNO dynamic intestinal model-1 (TIM-1). Preparation of RA-PLC was confirmed using X-ray diffraction, Fourier-transform infrared spectroscopy, partition coefficient measurement, and Caco-2 monolayer permeation test. Bioaccessibility parameters in different GIT compartments were investigated. Complexation by phospholipids reduced the bioaccessibility of RA in jejunum compartment, while maintaining the ileum bioaccessibility. The overall bioaccessibility of RA-PLC was lower than the unformulated drug, suggesting that the improved oral absorption from a previous animal study could be considered as a net result of decreased bioaccessibility overwhelmed by enhanced intestinal permeability. This study provides insights into the effects of phospholipid on the bioaccessibility of hydrophilic compounds, and analyzes them based on the relationship between bioaccessibility, membrane permeability, and bioavailability. Additionally, TIM-1 shows promise in the evaluation of dosage forms containing materials with complicated effects on bioaccessibility.